The overall goal is to demonstrate a link between mercury (Hg) exposure and elevated risks of autoimmune disease. In this project, we will test two hypotheses in translational research linking basic research in an animal model of autoimmune disease and an ongoing epidemiological study in two Hg-exposed human populations in Amazonian Brazil. The hypotheses are that 1) exposure of mice to Hg, at low dose, can result in changes iti the innate immune response to infection such that ultimately post-infection autoimmune disease is exacerbated in terms of severity and prevalence and 2) exposure of humans to Hg, at low dose, can result in changes in the immune system that are measurable and indicative of elevated risk of autoimmune dysfunction. Autoimmune diseases are among the most devastating chronic diseases in the US. While autoimmune diseases are recognized to involve both heritable and acquired risk factors, relatively littie Is known about the latter risks for human disease aside from exposure to infectious agents. These are believed to trigger the development of autoimmune diseases, but the expression and severity of disease may be a reflection of pre-existing genetic susceptibility in the context of ongoing environmental exposures (such as exposure to Hg). This project will assess programming changes that occur during the innate immune response to infection following exposure (during fetal development) to Hg, with an overall effect on the progression of coxsackievirus-induced autoimmune heart disease in mice and applying the biomarkers mined from these animal studies to a Hg-exposed human population in Amazonian Brazil (a riverine population exposed through fish consumption). Specific Aim 1. To test the hypothesis that fetal (murine) exposure to Hg induces changes in the immune system that affect the adult innate immune response to coxsackievirus infection and subsequent development of _ autoimmune disease. Specific Aim 2. To test the hypothesis that human exposure to Hg induces changes in the immune system that are measurable and indicative of elevated risk of autoimmune dysfunction.